NFNF 3812

Quality Control of Medicines

Part 1

AP Dr. Mazlina Mohd Said

Faculty of Pharmacy
UKM
 WHAT YOU SHOULD
KNOW?
▪ Why are the raw material / supplier qualifications getting more
concerns?
▪ What are the regulatory requirements available?

▪ How are we currently qualifying raw materials?

▪ What are the challenges and questions?

▪ What is the need for a guideline from FDA or USP?

THE CONCERNS FOR RAW MATERIAL / SUPPLIER
QUALIFICATIONS HAVE BEEN AMPLIFIED BY:

MATERIAL SUPPLY ISSUES

GLYCERIN – CONTAMINATED
AND/OR ADULTERATED WITH
DIETHYLENE GLYCOL (DEG)
▪ 109 children died in Nigeria in 1990, after taking DEG tinted
medicine

▪ Dozens of children in Haiti died a decade ago after taking DEG

contaminated medicine for fevers

▪ 365 people were killed in Panama in 2006 from toothpaste

containing DEG used as glycerin in a government factory

▪ “84 Children Are Killed by Medicine in Nigeria” (The New York

Times, February 6, 2009) taking My Pikin Baby Teething Mixture
for teething pain contained diethylene glycol
HEPARIN - CONTAMINATED AND/OR
ADULTERATED WITH OVERSULFATED
CHONDROITIN SULFATE (OSCS)
▪ In March 2008, major recall of heparin were announced by the FDA
due to contamination of the raw heparin stock imported from China.

▪ According to the FDA, the contaminated heparin killed 81 people in

the United States.

▪ In November 2008, the FDA seized eleven lots of heparin from Celsus
Laboratories Inc.
MELAMINE CONTAMINATIONS /
ADULTERATION IN PET FOOD AND
MILK PRODUCTS
▪ In 2007, more than 8,000 deaths of cats and dogs that may be
linked to melamine-tainted food

▪ In 2008, melamine-tainted milk products have poisoned

more than 53,000 children in China,

▪ Macao, Hong Kong, and Taiwan, and are responsible for at

least 3 (actual number: unknown) deaths by Oct. 2, 2008
SENDAYU TINGGI -SLIMMING
HERBAL DRINK
REGULATORY REQUIREMENTS :

RAW MATERIALS
QUALIFICATIONS
(1) CONTROL OF DRUGS AND COSMETICS
REGULATION 1984
Part IV (Manufacture of Registered Products)

Registered products shall be manufactures, processed, packed, labeled and

tested in premises which are in accordance with the standard set by the
authority

Adequate storage areas shall be provided so that all starting, returned or

rejected materials, or intermediate or finishes registered products, are
adequately separated

Manufacturing operations shall be carried out in accordance with such

requirements as may be determined by the authority

A QC department shall:
-Control all materials used in the manufacturing process
-Monitor the quality aspects of all manufacturing steps
 (II) USFDA CGMP - CODE OF FEDERAL
REGULATION (CFR)
21 CFR 210 & 211: cGMP for Finished Pharmaceuticals

▪ Subpart E – Control of Components and Drug Product

Containers and Closures

▪ §211.80 – §211.94

▪ Emphasized on procedures for the receipt, identification,

storage, handling, sampling, testing, and approval or
rejection

▪ No mention on the Evaluation or Qualification

 (III) FOOD AND DRUG
ADMINISTRATION (FDA)
Guidance for Industry - Quality Systems Approach to Pharmaceutical
CGMP Regulations, Sept. 2006

▪ FDA’s current thinking on 21CFR 210 and 211 recommends:

IV. THE QUALITY SYSTEMS MODEL

C. Manufacturing

2. Examine Inputs (any materials into a final product)

A robust quality system will ensure that all inputs to the manufacturing process
are reliable because quality controls will have been established for the receipt,
production, storage, and use of all inputs. The quality systems approach also
calls for periodic auditing of suppliers based on risk assessment.
 (III) FOOD AND DRUG
ADMINISTRATION (FDA)
FDA API Process Inspection – Compliance Program
Guidance Manual. Feb. 12, 2008

PART I - BACKGROUND (General):

▪ No distinction is made between an API and a finished
pharmaceutical in the Act and the failure of either to comply
with CGMP constitutes a violation of the Act.

▪ FDA has long recognized that the CGMP requirements in the

good manufacturing practice regulations for finished
pharmaceuticals (21 CFR Parts 210 and 211) are valid and
applicable in concept to Active Pharmaceutical Ingredient (API)
manufacturing.

PART II - IMPLEMENTATION (Program Management Instructions):

3. Materials System includes measures and activities to control
starting materials, intermediates, and containers.
(IV) International Conference of Harmonization (ICH)

Q7 GMP for Active Pharmaceutical Ingredients

In addition to the similar requirement as in 21CFR 211, the following says:

7. MATERIALS MANAGEMENT
7.1 General Controls

7.11 Manufacturers of intermediates and/or APIs should have a system for

evaluating the suppliers of critical materials.

7.31 Supplier approval should include an evaluation that provides adequate

evidence (e.g., past quality history) that the manufacturer can consistently
provide material meeting specifications. Full analyses should be conducted
on at least three batches before reducing in-house testing.
(IV) International Conference of Harmonization (ICH)

Q9 QUALITY RISK MANAGEMENT

Annex II: Potential Applications for Quality Risk Management

II.5 Quality Risk Management as Part of Materials Management

Assessment and evaluation of suppliers and contract manufacturers

To provide a comprehensive evaluation of suppliers and contract

manufacturers (e.g., auditing, supplier quality agreements).
(IV) International Conference of Harmonization (ICH)
Q10 PHARMACEUTICAL QUALITY SYSTEM

2.7 Management of Outsourced Activities and Purchased Materials

The pharmaceutical company is ultimately responsible to ensure

processes are in place to assure the control of outsourced activities
and quality of purchased materials.

(a) Assessing prior to outsourcing operations or selecting material

suppliers, the suitability and competence of the other party to carry
out the activity or provide the material using a defined supply chain
(e.g., audits, material evaluations, qualification);

(d) Monitoring incoming ingredients and materials to ensure they

are from approved sources using the agreed supply chain.
(v) ISO 9001:2008

Section 7.4 purchasing

7.4.1 Purchasing process

The organization shall ensure that purchased product

conforms to specified purchase requirements.
The organization shall evaluate and select suppliers based
on their ability to supply product in accordance with the
organization’s requirements. Criteria for selection, evaluation
and re-evaluation shall be established. Records of the results
of evaluations and any necessary actions arising from the
evaluation shall be maintained.
SUMMARY OF THE REGULATORY
REQUIREMENTS
Combining the requirements from different regulatory
bodies, it is summarized as:
▪ System
▪ Procedures
▪ Evaluations (or qualification)
▪ Record (Document)
▪ Auditing
▪ Monitoring

Ultimately responsibility-Pharmaceutical Company

No guidelines provided for how to realize these.
QUALITY ASSURANCE:
RAW MATERIALS
 CRITICAL PARTS OF DRUG
PRODUCTS

▪ Active Pharmaceutical Ingredients (APIs)

▪ Excipients
▪ Drug product containers

▪ Container closures (e.g.: ports, stopper, cap)

▪ Labeling (e.g.: inks, adhesives, label matrix)

To ensure the quality and safety of a drug product, all these

parts/materials and their suppliers should be qualified prior to
use.
PROCESS FLOW OF PHARMAC

QC sampling

QC tests
Quarantine Usable dock

Record: Dispensing
Supplier‘s
QC spec. name/code
Order no
QC Supplier’s
Purchasing batch / ref
RAW MATERIALS

Manufacture
dept. no
Quantity/ no
Approved of container
supplier
Purchase
order

Production Check
delivery :
Goods inward Labelled ID
(as PO)
Constituent
Quantity
 GENERAL CONTROL
Written procedures describing:

▪ The receipt

▪ Identification
▪ Quarantine

▪ Storage
▪ Handling
▪ Sampling

▪ Testing
▪ Approval or rejection of materials
 ▪ Documents that state standards which different materials
(1) SPECIFICATIONS OF RAW
should meet.

▪ Describe tests to carried out to show compliance with those

standards.

▪ Ensure identity, purity, potency of RM. Thus quality, safety &

efficiency of finishes products
▪ For purchasing
▪ For testing and retesting

RM specification & test procedures

MATERIALS

Pharmacopoeial monograph (BP, USP, JP)

Official reference (WHO)
In-house specification
(2) RAW MATERIAL (RM) SUPPL ▪ System to evaluate especially the supplier of critical RM
▪ Recommend at least 2 suppliers for each RM
▪ Compliance with cGMP requirement

Visit supplier’s facility (for audit)

Personnel & training modules, Documentation, Premise

& facilities, Manufacturing procedures & processes,
Complaints & recalls, Good QC lab practice

Visit at least once before purchase of raw material

and then periodically
 Alternatives to the audit
Performance history of supplier
(2) RM SUPPLIERS (CONT.)

▪ Past records of supply

Certification of supplier
▪ Referrals from government regulatory evaluations

ICH Q7 GMP for Active Pharmaceutical

Ingredients
ISO 9001: 2008 (section 7.4)
 (a) By authorized personnel only
(b) Physical examination
▪ Labeled ID of all goods – against PO & DO
▪ Quantity – against PO & DO
▪ Condition of goods
▪ Appearance
▪ Sign of external damage or spoilage, soiling or
dampness
▪ Integrity of seals
(3) RECEIPT OF

(c) Labelled (in-house) on each container

◦ Quarantine
◦ Released
◦ Rejected
(d) Quarantine label
◦ Code number
RM

◦ Name of material
◦ Lot number
 Example : SOP
Receipt of raw and packing
materials
Example :
Labels
 (e) Verification of compliance for quality

I) Supplier’s certificate of analysis (COA)

(3) RECEIPT OF RM

▪ Lab or organization issuing it

▪ Authorised by a competent person
▪ State material & batch number
▪ Who & when material tested
▪ Specification used & test method
▪ Test results & assertion that results showed compliance w
stated specification
 (e) Verification of compliance for quality

II) RM sampling

▪ Sampling procedure in accordance with approved written

procedures, in order to avoid and/or detect contamination.
(3) Receipt of RM

▪ Sampling plans
▪ Method, equipment & amount of test material
▪ Type & condition of sampling equipment
▪ Storage condition of materials
▪ Cleaning & storage of sampling equipment
▪ Risk & prevention of cross contamination during sampling
▪ Special precaution for sterile and hazardous material
▪ Instruction for re-sealing of opened container
 (e) Verification of compliance for quality

iii. QC testing
▪ Each lot or batch of RM is tested:
- To confirm the identity of the raw materials.
- To provide assurance that quality of the drug in dosage form will
(3) Receipt of RM

not be altered by RM defects.

- To assure that RM have the characteristics that will provide the
desired quantity or yield in manufacturing process.
▪ Testing procedure/method:
- Based on specified methods & limits
- Using validated test method

▪ Record of information :
- Name of RM tested
- Test methods, materials & instruments
- Test results
- Date of test & re-test
- Expiry date or shelf life
http://www.pharmaguideline.com/2011/02/sop-for-sampling-of-raw-
material.html
SAMPLING TOOLS
SAMPLING TOOLS
4) RELEASED & STORAGE
▪Only QC department authorises release or
rejection of tested materials
▪ Released – moved into usable stock area of
stores
▪ Rejected – moved into secure reject store
• Storage of RM
• Suitable condition (temperature, humidity, light
intensity)
• Well- cleaned & avoid cross-contamination
• Restricted access
F RM
 ▪ Materials should be re-evaluated as appropriate to
determine their suitability for use (e.g. after prolonged uses
or exposed to heat or humidity)
(5) RE-EVALUATION
 CHALLENGES FOR RAW
MATERIAL QUALIFICATIONS
▪ Lack of sufficient guidelines
▪ Costly process
▪ Un-intentional and/or intentional contamination

▪ Confidently consideration for information sharing

▪ Limited ability of auditing (time, language barriers and potential
selective exposures)
▪ Regional political environment: an open (information sharing and
monitoring) or a closed society